(a) Field of Invention
This invention relates to prostaglandin derivatives. More specifically this invention relates to 9,15-dioxygenated derivatives of prost-5-enoic and prosta-5,13-dienoic acid having optional alkyl substituents, to lower alkyl esters thereof and to homologs thereof. Also encompassed within this invention are processes for preparing these compounds and intermediates used therein.
(B) Description of the Prior Art
The chemistry and pharmacological effects of the prostaglandins have been the subject of several recent reviews; for example, see E. W. Horton, Physiol. Rev., 49, 122 (1969), J. F. Bagli in "Annual Reports in Medicinal Chemistry, 1969", C. K. Cain, Ed., Academic Press, New York and London, 1970, p. 170, and J. E. Pike in "Progress in the Chemistry of Organic Natural Products", Vol. 28, W. Herz, et al. Eds., Springer Verlag, New York, 1970, p. 313.
Due to the increasing interest in these natural products a rather extensive effort has been given recently to the synthesis of prostaglandins and their analogs. Included among these syntheses are several synthetic methods for the preparation of 9,15-dioxygenated derivatives of prostanoic or prost-13-enoic acid. For example, the synthesis of the first pharmacologically active 9,15-dioxygenated prostanoic acid derivative, 9.beta.,15.xi.-dihydroxyprost-13-enoic acid (11-desoxyprostaglandin F.sub.1.beta.) was reported in detail by J. F. Bagli, T. Bogri and R. Deghenghi, Tetrahedron Letters, 465 (1966). A significant simplification and modification of that process was described by Bagli and Bogri in U.S. Pat. No. 3,455,992, issued July 15, 1969, whereby 9.beta.,15.xi.-dihydroxyprost-13-enoic acid as well as homologs thereof were obtained, see also Bagli and Bogri, Tetrahedron Letters, 5 (1967).
Further improvements in the synthesis of 9,15-dioxygenated derivatives of prostanoic acid have been described by Bagli and Bogri in Tetrahedron Letters, 1639 (1969) and German Offenlegungsschrift No. 1,953,232, published Apr. 30, 1970, and in British Pat. Specification No. 1,097,533, published Jan. 3, 1968.
More recently, Bagli and Bogri have extended the scope of their processes for preparing 9,15-dioxygenated derivatives of prostanoic acid to include the preparation of 9-oxo-15-hydroxy prostanoic acid derivatives having an alkyl substituent at position 15, U.S. Pat. No. 3,671,570, issued June 20, 1972. These 15-alkyl derivatives possess hypotensive, antihypertensive, bronchospasmolytic and gastric acid secretion inhibiting properties, as well as inhibiting the aggregation of platelets and promoting the disaggregation of aggregated platelets.
Still further improvements in the synthesis of such 9,15-dioxygenated derivatives are described in U.S. Pat. No. 3,773,795, issued Nov. 20, 1973, U.S. Pat. application Ser. No. 351,381, filed Apr. 16, 1973 and the publication by N. A. Abraham, Tetrahedron Letters, 451 (1973).
Other recent syntheses of 9,15-dioxygenated derivatives are reported in Belgian Pat. No. 766,521, published Nov. 3, 1971, P. Crabbe and A. Guzman, Tetrahedron Letters, 115 (1972), M. P. L. Caron, et al., Tetrahedron Letters, 773 (1972), C. J. Sih, et al., Tetrahedron Letters, 2435 (1972), F. S. Alverez, et al., J. Amer. Chem. Soc., 94, 7823 (1972), A. F. Kluge, et al. and J. Amer. Chem. Soc., 94, 9256 (1972).
It is noteworthy that the synthetic 9,15-dioxygenated prostanoic acid derivatives described above possess a number of the biological activities of the natural compounds although they lack the 11-hydroxyl of the latter.
In addition it should be noted that the natural PGE.sub.1, PGE.sub.2, PGF.sub.1.alpha. and PGF.sub.2.alpha. do have the disadvantage of being relatively unstable, see T. O. Oesterling, et al., J. Pharm. Sci., 61, 1861 (1972). For example, it is well known that the 11-hydroxy group of PGE.sub.1 and PGE.sub.2 participates readily in dehydration reactions under both basic and acidic conditions, see S. Bergstrom et al., J. Biol. Chem. 238, 3555 (1963), E. J. Corey et al., J. Amer. Chem. Soc., 90, 3245 (1968), J. E. Pike et al., J. Org. Chem. 34, 3552 (1969) and "The Prostaglandins, Progress in Research", S. M. M. Karim, Ed., Wiley-Interscience, New York, 1972, p. 10.
As realized by those skilled in the art this inherent disadvantage of the natural compounds must always be taken into account when considering the practical aspects of preparation, formulation or storage of these compounds. In contrast, the compounds of the present invention are free from this disadvantage.
It is the purpose of the present disclosure to describe certain 9,15-dioxygenated prostanoic acid derivatives possessing useful pharmacologic properties coupled with a relatively low order of toxicity. Furthermore, there is disclosed a process for preparing the derivatives which starts from readily available starting materials, avoids noxious agents, is executed facilely and is adaptable to large scale preparation of the derivatives.
For example, the present process utilizes as one of its starting materials a dialkyl 2-(carboalkoxymethyl)malonate (formula 3, see below), which is readily prepared by condensing a dialkyl malonate with the appropriate readily available lower alkyl haloacetic acid. The ready availability of this starting material represents an improvement over our earlier process of U.S. Patent application Ser. No. 238,650, filed Mar. 27, 1973 (see also corresponding West German Offenlegungsschrift No. 2,313,686, published Apr. 10, 1973). The earlier process utilizes a substituted malonate derivative which in some cases takes a seven or eight step synthesis to prepare.
Other advantages of the present process are that it yields directly prostaglandin derivatives having the hydroxy group of the cyclopentane ring in the most desirable configuration. In other words the more active epimer with respect to the configuration of the cyclopentane hydroxy group is obtained. Furthermore, this desirable result can be achieved with simple and non-hazardous reagents, for example by reducing the appropriate precursor ketone with sodium borohydride, thereby eliminating the necessity of using noxious or expensive reagents; cf. E. J. Corey, et al., J. Amer. Chem. Soc., 93, 1491 (1971).
Still another advantage of the present process features the preparation of an entirely new class of prostaglandin derivatives in which the acid side chain is unsaturated and the side chain bearing the hydroxy group is fully saturated.
The foregoing advantages render the prostaglandin derivatives of this invention particularly desirable as pharmacologic agents.